Cocaine dependence is a problem of national significance. In the past decade there has been a considerable advance in the understanding of the chemistry and pharmacology of cocaine dependence. Notwithstanding, no cocaine pharmacotherapy has yet been approved by the FDA. A number of lead compounds are undergoing pharmacological evaluation as potential therapeutic agents. Cocaine's reinforcing properties and stimulant effects are associated with its propensity to bind to monoamine transporters. The goal of this project is to design potential pharmacotherapies for cocaine dependence. We will focus on the development of an understanding of the interaction between ligand and monoamine neurotransmitter uptake systems. We propose to expand our search for compounds that bind to DAT and SERT mechanisms but disturb dopamine (DA) uptake minimally, for compounds with slow onset and long duration of action, and for mechanism-based inhibitors of cocaine binding. We will focus on three classes: 8-oxabicyclo[3,2,1]octanes (oxatropanes), 8-azabicyclo[3,2,1]octanes (tropanes) and pyrovalerone analogues. The Specific Aims are: Synthesis and evaluation of (i) non-nitrogen tropane analogs, (ii) 6- and 7 hydroxylated 8-azatropane prodrugs, (iii) 6- and 7-hydroxylated 8-oxatropan(en)es, (iv) dopamine sparing cocaine antagonists that bind irreversibly to the cocaine site, (v) 3-heterobiaryltropanes. (vi) analogues of pyrovalerone.